17alpha-butatrienyl steroids

ABSTRACT

17X-BUTATRIENYL-ESTRA-1,3,5(10)-TRIENE STEROIDS AND 17A-BUTATRIENYL-ANDROST-4-ENE AND 17A-BUTATRIENYL-19-NORANDROST-4-ENE STEROIDS AND METHODS OF MAKING THESE COMPOUNDS. THE COMPOUNDS ARE PREPARED FROM THE CORRESPONDING 17X-(2&#39;&#39;,3&#39;&#39;-DIHALOMETHYLENEPROP-1&#39;&#39;-EN-1&#39;&#39;-YL) STEROID COMPOUNDS BY DEHALOGENATION AND REARRANGEMENT OF THE 17A-DIHALOCYCLOPROPYL GROUP INTO A PROPADIENE GROUP THEREBY AFFORDING THE ABOVE BUTATRIENE COMPOUNDS. THE ABOVE 17A-BUTATRIENYL-ESTRA-1,3,5(10)-TRIENE STEROIDS HAVE UTILITY IN PALLIATING CONDITIONSARISING IN MAMMALS WHICH ARE CAUSED BY OR RELATED ESTROGEN DEFICIENCY. THE 17A-BUTATRIENYL-ANDROST-4-ENE AND 17X-BUTATRIENYL-19NORANDROST-4-ENE STERODIS ARE USEFUL FOR PALLIATIG MENSTRUAL DISORDERS AND IN THE CONTROL AND REGULATION OF FERTILITY IN MAMMALS.

United States Patent @fice 3,661,943 Patented May 9, 1972 ABSTRACT OF THE DISCLOSURE l7a-butatrienyl-estra 1,3,5( 10) triene steroids and 17a-butatrienyl-androst-4-ene and 17a-butatrienyl-19-norandrost-4-ene steroids and methods of making these compounds. The compounds are prepared from the corresponding 117a+(2',3-dihalomethyleneprop-1'-en 1 yl) steroid compounds by dehalogenation and rearrangement of the 17u-dihalocyclopropyl group into a propadiene group thereby aifording the above butatriene compounds. The above 17a-butatrienyl-estra-1,3,5(10)-triene steroids have utility in palliating conditions arising in mammals which are caused by or related to estrogen deficiency. The 17a-butatrienyl-androst 4 ene and 17a-butatrienyl-19- norandrost-4-ene steroids are useful for palliating menstrual disorders and in the control and regulation of fertility in mammals.

BACKGROUND OF THE INVENTION (1) Field of the invention This invention relates to 17a-butatriene steroids and to methods of making such steroids. In a further aspect, this invention relates to 17a-butatatrien-estra-1,3,5(10')- triene compounds and to methods of preparing such compounds. In a still further aspect this invention relates to 17a-butatrieny1-androst 4 ene and 17a-butatrienyl-19- norandrost-4-ene compounds and to methods of preparing such compounds.

(2) The prior art 17a-propadien-estrane and 17a-propadien-androstane I In summary, the compounds of my invention can be represented by the following generic formula:

wherein R is hydroxy, carboxylic acyloxy group having less than 12 carbon atoms, or acid labile ether group having less than 12 carbon atoms such as, for example, tetrahydrofuran-Z-yloxy, tetrahydropyran-Z-yloxy, or 4- methoxytetrahydropyran-4-yloxy; R and R are independently H or lower alkyl; R and R are independently H, or lower alkyl; and Z is wherein R is hydroxy, carboxylic acyloxy group having less than 12 carbon atoms, lower 'alkoxy group having less than 12 carbon atoms such as, for example, methoxy, ethoxy or cyclopentyloxy, or acid labile ether group having less than 12 carbon atoms such as, for example, tetrahydropyran-Z-yloxy, or tetrahydrofuran-Z-yloxy; R is H or methyl and R is 0x0 or the group wherein R is hydrogen, lower alkyl, hydroxy, acyloxy group having less than 12 carbon atoms, lower alkoxy group having less than 12 carbon atoms such as, for example, methoxy, ethoxy or cyclopentyloxy, or acid labile ether groups having less than 12 carbon atoms such as, for example, tetrahydropyran 2 yloxy, tetrahydrofuran-Z-yloxy and 4'-methoxytetrahydropyran-4'-yloxy.

In summary, the compounds of my invention can be prepared by the dehalogenation and rearrangement of the dihalocyclopropyl group-in the corresponding 17a.- (2',3' dihalomethylene-propyl l'en-lyl) steroid compounds-into the corresponding propadiene group. This can be effected by any suitable treatment such as, for example, by treating the corresponding 17a-diha1ocyclopropyl compound With; (1) magnesium in an inert organic reaction medium; or (2) a suitable alkylsulfinyl carbanion in an inert organic solvent; or (3) potassium t-butoxide in an inert organic solvent; or (4) a suitable alkyl lithium in an inert organic solvent; or (5) cuprous chloride in a suitable inert organic solvent.

The above compounds and processes will be further discussed hereinbelow.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS The 17a-butatrienyl-estra-1,3,5(10)-triene steroid compounds of my invention can be represented by the following formula:

wherein R is hydroxy, carboxylic 'acyloxy group having less than 12 carbon atoms, acid labile ether group having less than 12 carbon atoms such as, for example, tetrahydrofuran-2'-yloxy, tetrahydropyran 2' yloxy, or 4'- methoxytetrahydropyran-4'-yloxy; R R R and R are independently H, or lower alkyl; and R is hydroxy, carboxylic acyloxy group having less than 12 carbon atoms, lower alkoxy group having less than 12 carbon atoms such as, for example, methoxy, ethoxy or cyclopentyloxy, or acid labile ether group having less than 12 carbon atoms such as, for example, 4' methoxy-tetrahydropyran-4- yloxy, tetrahydropyran-2-yloxy, or tetrahydrofuran-2'- yloxy.

- 3 In the preferred'compounds of Formula II, R is hydroxy, methoxy or acetoxy; R is hydroxy or acetoxy; R is H or methyl and R and'R are independently H or methyl. Particularly preferred compounds of Formula II, include 3-acetoxy-17 3-hydroxy-171x-(4',4'-dimethyl-butatrienyl) estra-l,3,5()-triene; v a

3,17p-diacetoxy-17a-(4',4-dimethy1-butatrienyl) -estra- 1,3,5 10)-triene;

3, 17 3-dihydroxy-17a-( 1-methyl-butatrienyl) -estra-1,

3,5 10) -triene;

'17,8-acetoxy-3-hydroxy-17a-(1-methy1-butatrienyl)- estra-1,3,5(10)-triene; 17fl-acetoxy-17m-butatrienyl-3-hydroxy-estra-1,3,5 10 triene;

17 8-acetoxy-17a-butatrienyl-3methoxy-estra-1,3,5 10) 1 triene; 3,17B-diacetoxy-17a-butatrienyl-estra-1,3,5 (10)-triene; 17a-butatrienyl-3, 17 B-dihydroxy-estral ,3 ,5 (10)-triene; 17a-butatrienyl-l7B-hydroxy-3-rnethoxy-estra-1,3 ,5 10

triene; and 3-acetoxy-17a-butatrienyl-17B-hydroxy-estra- 1,3 ,5 10) triene.

The androstane or 19-norandrostane steroid compounds of my invention can be represented by the following formula:

(III) wherein R R R R R have the same meaning as set forth hereinabove; and R is H or methyl and R is 0x0 or the group wherein R is hydrogen, hydroxy, acyloxy group having less than 12. carbon atoms, lower alkoxy group having less than 12 carbon atoms such as, for example, methoxy, ethoxy or cyclopentyloxy, or acid labile ether .group having less than 12 carbon atoms such as, for example, tetrahydropyran-2'-y1oxy, tetrahydrofuran-2-yloxy and 4-methoxytetrahydropyran-4'-yloxy.

The preferred compounds of Formula III are those wherein R is hydroxy or acetoxy; R is H or methyl; R is H or methyl; R and R are independently H or methyl; R is H or methyl; and R is oxo or the group wherein R is H, hydroxy or acetoxy. Typical preferred compounds include, for example,

17a-butatrienyl-17/3-hydroxy- 1 8-methyl-19-norandrost- 4-en-3-one;

1718-acetoxy-17u-butatrienyl-l9-norandrost-4-en-3-one;

17,8-acetoxy- 17 a-butatrienyl- 18-methy1-19-norandrost- 4-en-3-one;

l7a-butatrienyl- 17 fl-hydroxy-androstl-ene;

17u-butatrieny1-l7fi-hydroxy-18-methyl-androst-4-ene;

17,B-acetoxy-17a-butatrienyl-androst-4-ene;

l7fi-acetoxy-17a-butatrienyl-18-methyl-androst-4-ene;

17 ,B-hydroxy-l 7:1- (4',4'-dimethy1-butatrienyl) 1 9-1101- androst-4-en-3-one;

17 8-hydroxy-17a-(4',4-dimethyl-butatrienyl)-18-methyl-l9-norandrost-4-en-3-one;

17fl-acetoxy-17a-(4',4'-dimethyl-butatrienyl)-19-norandrost-4-en-3-one;

17fl-3C61ZOXY-17oz- (4,4-dimethyl-butatrienyl) -18-methyl- 19-norandrost-4-en-3-one;

17/8-hydroxy-17a-(1'-methy1-butatrienyl)-19norandrost- 4-en-3-one;

17,6-hydroxy-17a- 1-methyl-butatrienyl-18-methyl- 19-norandrost-4-en-3-one;

17B-acetoxy-17a-(1'-methyl-butatrienyl)19-norandrost- 4-en-3-one;

17fl-acetoxy-17a-(1'-methyl-butatrienyl)-18-mcthyl-19- norandrost-4-en-3-one;

17/3-hydroxy-17a-( 1',4',4'-trimethyl-butatrienyl) 19- norandrost-4-en-3-one;

17 fl-hydroxyl7a( 1',4,4'-trimethyl-butatrienyl -1 8- methyl- 19-norandrost-4-en-3-one;

17fl-acetoxy- 17 oc- 1 ',4',4'-trimethyl-butatrienyl 19- norandrost-4-en-3-one; and

17B-acetoxy-17a-( l,4',4'-trimethyl-butatrienyl)-18- methyl-19-norandrost-4-en-3 -one.

Of the above listed preferred compounds of Formula III, the following compounds are particularly preferred,

17a-butatrienyl-17,8-hydroxy-19-norandrost-4-en-3-one;

17a-butatrienyl-17,9-hydroxy-18-methyl-19-norandrost- 4-en-3-one;

17,13-hydroxy- 17 a-( 1'-methyl-butatrienyl -19-norandrost- 4-en-3-one; and

l7/3-hydroxy- 1 7a-( 1-methy1-butatrienyl)-18-methyl- 19-norandrost-4-en-3-one.

The compounds of Formula II of my invention possess estrogenic activity and are useful in the treatment of various conditions related to estrogen deficiency such as, for example, menopause syndrome. These compounds can also be used in veterinary medicine in the same manner as known estrogenic agents and in the control and regulation of fertility. In addition, these agents demonstrate antiandrogenic activity. They can be administered in the usual pharmaceutical compositions at dosages appropriate for the condition and subject being treated.

The compounds of Formula III of my invention demonstrate progestational, anti-estrogen activity and pituitary inhibition activity and are useful in the treatment. of various menstrual disorders and in the control and regulation of fertility. They can be administered in the usual pharmaceutical compositions at dosages appropriate for the condition and subject being treated.

The following terms as used hereinabove and below, have the following meanings. The term acyloxy refers to acyloxy groups conventionally employed in the synthetic hormone art containing from 1 to 12 carbon atoms. Typical acyloxy ester groups include, for example, acetate, propionate, butyrate, valerate, caproate, enanthate, benzoate, diphenylacetate, diethylacetate, trimethylacctate, and the like. The term lower alkyl refers to straight and branched saturated aliphatic groups containing from one through six carbon atoms such as, for example, methyl, ethyl, isopropyl, and the like. The term lower alkoxy refers to straight and branched chain alkoxy groups containing from one to twelve carbon atoms such as, for example, methoxy, ethoxy, propoxy, and the like. The term acid labile ether refers to acid labile ether groups having less than 12 carbon atoms such as, for example, tetrahydropyran-2-yloxy; tetrahydrofuran 2 yloxy and 4'- methoxytetrahydropyran-4'-yloxy. The term halo refers to the halogen atoms fiuoro; chloro; bromo; and iodo.

The compounds of my invention can be prepared from the corresponding 17a-(2',3-dihalomethylene-prop-1'-en- 1-yl) steroid compounds by any suitable process which will effect the dehalogenation and rearrangement of the 2,3-dihalomethylene-prop-1-ene grouping into the corresponding butatriene group. I have further found that best results are obtained in terms of ease of preparation and product recovery by using the 2',3-dichloromethylene; chlorohalomcthylene; dibromomethylene or bromohalomethylene precursor as compared with the difluoromethylene, diiodomethylene or fiuoroiodomethylene precursors and thus pragmatically the former precursors will typically be used. The preferred dehalogenation and rearrangement conversion can be represented (using partial steroid formulas) by the following schematic overall reaction equation:

wherein R R R R R and X have the same meanings as set forth hereinabove and Y and X are independently chloro; bromo or wherein when one of Y and X is chloro or bromo, the other can be iodo or fluoro.

I have found that suitable methods for effecting the aforementioned conversion include, for example, treating the corresponding 17oz (2',3'-dihalomethylene-prop-1'- ene) compound of Formula (B) with potassium t-butoxide in an inert organic solvent. The treatment is typically conducted at temperatures of about 20 C. or above for about from 2 to 24 hours, with best results being obtained using the reflux temperature of the system. The relative mol ratio of reactants will typically be in the range of about from 2 to 20 mols of potassium t-butoxide per mol of l7a-(2,3-methylene-prop-l-ene) steroid starting material though mol ratios both below and above this can be used. Suitable inert organic solvents include, for example, dimethylsulfoxide, diethylether, tetrahydrofuran and the like. The product can then be separated from the reaction mass and further purified by any suitable procedure such as, for example, chromatography over silica gel or alumina and crystallization.

The overall conversion (b) can also be elfected b treating the starting material of Formula (B) with an alkali metal alkylsulfinyl carbanion in an inert organic solvent.

The treatment is typically conducted using a dimethylsulfoxide solvent and temperatures in the range of about from 0 to 20 C. for about from 2 to 48 hours and for best results temperatures of about from 0 to C. and treatment times of 2 to 24 hours. The relative mol ratio of reactants is not critical but typically will be in the range of about from 2 to moles of alkali metal alkylsulfinyl carbanion per mol of l7a-cyclopropyl starting material and for best results mole ratios of about from 2 to 5. Suitable alkali metal alkylsulfinyl carbanions include, for example, sodium methylsulfinyl carbanion, lithium methylsulfinyl carbanion, potassium methylsulfinyl carbanion, and the like. Best results are obtained using sodium methylsulfinyl carbanion. Suitable organic solvents which can be used include, for example, dimethylsulfoxide, ether, tetrahydrofuran, dioxane, and the like. The product can be separated from the reaction mass and further purified by any suitable method such as, for example, chromography over silica gel or alumina and crystallization.

A third method of preparing the compounds of my invention includes treating the starting material of Formula (B) with activated magnesium in a suitable organic medium such as, for example, diethyl ether, tetrahydrofuran, dioxane, and the like, typically using temperatures in the range of about from 20 C. to reflux for about from 2 to 24- hours, with best results being obtained using the reflux temperatures. The compounds of my invention can also be prepared by treating the compounds of Formula (B) with an alkyl lithium such as, for example, butyl lithium, methyl lithium, t-butyl lithium and the like, in an inert organic solvent such as, for example, hexane, benzene, ether, monoglyme, diglyme, tetrahydrofuran, and compatible mixtures thereof. Particularly good results are obtained by the use of butyl lithium in an organic solvent mixture of tetrahydrofuran and hexane. The treatment is typically effected at temperatures of about from 20 C. or above for about from 3 to 24 hours with best results being obtained at temperatures in the range of about from 20 to C.

The compounds of our invention can also be prepared by a fifth method by treating the corresponding compounds of Formula B with copper chloride (CuCl) in dimethyl sulfoxide, or a suitable equivalent inert organic solvent, at temperatures in the range of about from 15 to C. for about from 10 to hours. Typically longer treatment times are required with lower temperatures and the treatment is further preferably conducted under a nitrogen atmosphere.

Separation and purification of the products in each of the aforementioned treatments can be effected by any suitable method such as, for example, chromatography over silica gel or alumina and crystallization.

The 170: (2,3 dihalomethylene-prop-l'-ene) starting materials of Formula B can be prepared from the corresponding 17a-pr0padiene compounds by any suitable method for adding of dihalomethylene bridge across the 2,3'-double bond in the propadiene group. This process can be represented (using partial steroid formuli) by the following overall schematic reaction equation:

wherein R R R R R X, Y and Z have the same meaning as set forth hereinabove.

This reaction can be conveniently effected by suitable dihalo carbene addition reactions for inserting a dihalomethylene bridge across a double bond. The dihalo carbene addition reaction can, for example, be effected by treating the propadiene compounds of Formula (A) with an alkali metal trihaloacetate in an inert organic solvent. This reaction is typically conducted at temperatures in the range of about from 80 to C. for about from 1 to 5 hours, with best results being obtained by using temperatures in the range of about from 120 to 160 C. for about 2 hours. The reaction is further preferably conducted under anhydrous conditions. The relative mol ratio of reactants typically is in the range of about from 10 to 50 mols of starting material (A) per mol of dihalo carbene generated by the dihalo carbene precursor, though mole ratios both above and below this can be used. Suitable alkali metal trihaloacetate include, for example, sodium trichloroacetate, sodium chlorodifluoroacetate, sodium tribro-moacetate, sodium dichloro fluoroacetate, potassium fluorodichloroacetate, potassium tribromoacetate, and the like. Suitable inert organic solvents include, for example, diglyme, monoglyme, tetrahydrofuran, and the like. The reaction product can be separated and purified by any suitable procedure such as, for example, chromatography over silica gel or alumina and crystallization.

Other suitable dihalo carbene generating reactions which can be used for preparing the starting material of Formula (B) include, for example, treatment of the corresponding 17a-propadiene compound with (1) trimethyl (trichloromethyl) tin, or trimethyl (trifiuoromethyl) tin or the like, in an inert organic solvent such as, for example, benzene, tetrahydrofuran, toluene, monoglyme, and the like, in the presence of sodium iodide, typically conducted at the reflux temperature of this system; or (2) phenyl (trihalomethyl) mercury, such as for example, phenyl (trichloromethyl) mercury or phenyl (brornodichloromethyl) mercury, typically in the presence or absence of sodium iodide, in an inert organic solvent such as, for example, benzene, at the reflux temperature of the system; and (3) bromoform in the presence of potassium t-butoxide and an inert organic solvent such as, for example, tetrahydrofuran, hexane, monoglyme and the like, typically using temperatures in the range of about from to 20 C. for about /2 to 10 hours, and reactant mole ratios in the range of about from 10 to moles of bromoform and 10 to 30 moles of potassium tbutoxide per mole of steroid and about one mole of bromoform per mole of potassium t-butoxide, though mole ratios both above and below these ratios can also be used.

Product separation in the above reactions can be achieved by any suitable method such as, for example, those described in US. Pats. 3,392,165 and 3,392,166. The propadiene starting materials are known materials and can be prepared, for example, according to the methods described in the aforementioned US. Patents.

Variation in the 3- and/or 17-position substituents of the compounds of my invention (Formulas II and III) can be effected either prior to or subsequent to the preparation of the compounds. Further, where the desired 17-position substituent is hydroxy or where the desired 3-position substituent is hydroxy or ketone, it is preferable (especially where the alkylsulfinyl carbanion or alkyl lithium treatments, described hereinabove) are to be used to convert the 3- or 17-position hydroxy or 3-position ketone starting material to a suitable cleavable,,base labile ester or acid labile ether prior to effecting the various dehalogenation and rearrangement treatments described hereinabove. The 17- and/or 3-position ester or ether product can then be easily restored to or converted to the desired 17-hydroxy and/ or 3-hydroxy or 3-ketone product by cleavage of the base labile ester or acid labile ether by any suitable procedure. Generally, it is preferable to use ether protecting groups such as, for example, tetrahydropyran-Z-yloxy and the like.

The 3,17B-dihydroxy steroid compounds of Formula I, or A or B can, for example, be converted to 3,17,8- diacyloxy derivatives by treatment with an acid anhydride and hot pyridine or p-toluenesulfonic acid. The diester derivative can be selectively saponified, either before or after conversion to the compounds of Formula I, for example, by the use of methanolic potassium bicarbonate, to yield the corresponding 3-hydroxy-17fi-acyloxy compound. The 3-ethers or 3,1713-diethers can be prepared by any suitable procedure for converting keto or hydroxy groups into ether groups. Thus, for example, treatment of 3- and/or 17B-hydroxy compounds with dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid, p-toluenesulfonyl chloride, dinitrobenzene sulfonic acid or the like, yields the corresponding 3,l7tetrahydropyran-Z-yloxy compounds. Formation of monotetrahydropyranyl ethers can be accomplished by selective protection of other hydroxy groups, for example, by ester formation, in the manner described above, followed by alkaline hydrolysis of such ester groups, after formation of the ether, if return of the esterified hydroxy group is desired. Formation of 3-methoxy derivatives can, for example, be achieved through the use of dimethylsulfate and potassium hydroxide in the conventional manner.

3-keto steroids can be reduced to the corresponding 3,?- hydroxy steroid by any suitable procedure, for example, by treatment with sodium borohydride, or lithium alumina tri-(t-butoxy) hydride. The resulting 3-hydroxy group can be etherified by treatment with dihydropyran or dihydrofuran and an acid catalyst or esterified by treatment with an appropriate carboxylic acid anhydride such as acetic acid anhydride, in pyridine or the like.

The l7 8-hydroxy estrenes or androstenes can be con verted to the corresponding 17,8-acyloxy or 17/3-tetrahydropyran-Z-yloxy, or 17fl-tetrahydrofuran-2-yloxy derivatives by conventional methods, such as those already set forth. The 3-desoxy derivatives (i.e. R is the group of the 3-keto compounds of Formula III can be prepared from the corresponding 3-keto derivatives by thioketalization followed by desulfurization with Raney nickel.

The 3-keto precursors of the compounds of Formula III can be conveniently protected by 3-methoxy-3,5-diene or 3ethyloxy-3,5-diene groups by treatment with methyl or ethyl orthoformate in a suitable inert organic solvent, e.g., dioxane, ether and benzene, in the presence of an acid catalyst, e.g. p-toluenesulfonic acid, benzenesulfonic acid, sulfosalicylic acid and the like. This treatment results in a 3-rnethoxy or 3-ethoxy-3,5(6)-diene steroid which is easily converted back to the 3-keto-4-ene steroid, typically after conversion of the 17a-dihalomethylene) steroid to the corresponding 17a-butatriene steroid, by treatment with a suitable acid, such as for example, bydrochloric acid, p-toluenesulfonic acid, oxalic acid and the like, in an aqueous organic solvent; such as, for example, aqueous acetone, aqueous methanol, aqueous tetrahydrofuran, and the like.

The use of protecting groups is well known to the art and further information can, for example, be obtained from the literature such as, for example, the aforementioned U.S. Pats. 3,392,165 and 3,392,166. Additional techniques for adding or changing protecting groups will thus be readily apparent to those skilled in the art.

A further understanding of my invention can be had from the following nonlimiting examples; wherein mmoles refers to gram millimoles, me. refers to gram milliequivalents, and temperatures are given in C.

EXAMPLE 1 This example illustrates methods of preparing 17a(2', 3'-dihalomethylene-prop-1-en-l'-yl) steroid starting materials for the compounds of my invention. In this example a sodium trichloroacetate solution is prepared by dissolving 20 mmoles of sodium trichloroacetate in 30 ml. of diglyme (distilled over potassium hydroxide pellets) and then vacuum distilling off 10 ml. of diglyme (using temperatures in the range of from 30 to 40 C.). A 174 (propadien-1'-yl) steroid solution is prepared by dissolving 1 mmole of 17/8-acetoxy-17ot-(propadien- -yl)-l9- norandrost-4-en-3-one in 17 ml. of diglyme. The 175- acetoxy-17a(propadien-1'-yl) 19 norandrost 4 en-3- one solution is heated to its boiling point and maintained at this temperature throughout the addition of the sodium trichloroacetate solution. The sodium trichloroacetate solution is slowly added dropwise to the steroid over a period of one hour, during this addition 40 ml. of diglyme is distilled from the reaction mixture (atmospheric pressure). The reaction mixture is then refluxed for 10 minutes, cooled, filtered and evaporated. The evaporation residue is subjected to preparative thick-layer chromatography, eluting with hexane-ethyl acetate (4:1 by vol.) affords crude 17fl-acetoxy-17ot-(2',3' dichloromethyleneprop-1-en-1-yl)-l9-norandrost-4-en-3-one which is then further purified by crystallization from acetone-ether.

By following the above procedure using the corresponding 17u-propadiene steroid starting materials, the following compounds are prepared:

l7li-acetoxy- 17a- 2', -dichloromethylene-1'-methylprop-1 -en-1-yl)-19-norandrost-4-en-3-one;

3-acetoxy-17ot-(2',3 '-dichloromethylene-1',3 '-dimethy1- prop-1'-en-1'-yl)-17;3-(tetrahydropyran-2'-yloxy)- cstra-1,3,5( -triene;

3-acetoxy-1704-(2',3'-dichloromethylene-1,3',3 '-trimethy1-prop-1'-en-1'-yl) -17fi-(tetrahydropyran- 2-yloxy) -estra-1,3,5( 10) -triene;

3-acetoxy- 17 oc- (2',3 '-dichloromethylene-prop-1'-en- '-yl 175- (tetrahydropyran-2-yloxy) -1 8-methy1- estra-1,3 ,5( 10)-triene;

3 -acetoxy-l 7a- (2', 3 '-dichloromethylene-1'-methyl-prop- 1-en-1'-yl)-17/3-(tetrahydropyran-2'-yloxy -l 8 -methyl-estra-1,3,5 10)-triene;

3-acetoxy-17e-(2',3 -dichloromethylene-3'-methyl-prop- 1-en-1'-yl) -175-(tetrahydropyran-2-yloxy) -l 8- methyl-estra- 1,3,5 10) -triene;

3-acetoxy-l7a- (2,3'-dichlorornethylene-3',3 '-dirnethylprop-1'-en-1-yl)-17 3-(tetrahydropyran-2'-yloxy) -18- methy1-estra-1,3,5 10 -triene;

3-acetoxy-17a-(2',3 '-dichlorornethylene-1,3 '-dimethylprop-1'-en-1'yl)-17/3-(tetrahydropyran-2'-yloxy)-18- methy1-estra-1,3 ,5 10) -triene;

3-acetoxy-17a-(2',3-dichloromethylene-1,3 ',3'-trimethylpropy-1'-en-1'-yl)-17fi- (tetrahydropyran-2'-yloxy) 18-methyl-estra-1,3 ,5 10) -triene.

By following the same procedure but using phenyl (dibromochloromethyl) mercury; phenyl -(tribromomethyl) mercury and phenyl (dibromofluoromethyl) mercury, respectively, the corresponding 17oz (2,3'-bromochloromethylene), 17a-(2,3-dibromornethylene) and 17u-(2', 3'-bromofluoromethylene) forms of the above compounds are, respectively, prepared.

EXAMPLE 3 This example illustrates further methods for preparing 17a-dihal0methylene steroid starting materials. In this example 20 me. of bromoform and 20 me. of potassium tbutoxide are added to a solution of 2 me. of 17fl-(tetrahydropyran 2' yloxy) 3-methoxy-17a-propadien-1'-yl)- estra-1,3,5 (10)-triene in 100 ml. of cyclohexane at 0 C., with stirring. The mixture is maintained at 0 C. for 6 hours then poured into water and extracted with ethyl acetate. The ethyl acetate extracts are evaporated affording a crude 17a-(2',3-dibromomethylene-prop-1'-en-1'- yl)-l75-(tetrahydropyran 2' yloxy)-3-methoxy-estra- 1,3,5(10)-triene residue which is then purified by chromatography over alumina eluting first with hexane-benzene mixture, and then with pure benzene.

By following the above procedure using the corresponding 17a-propadiene steroid starting materials, the follow- 5 ing compounds are prepared:

17a- (2',3 '-dibromomethylene-3 ',3'-dimethyl-prop-1-en- 1-yl) -17[3- (tetrahydropyran-2'-yloxy) -3-methoxy-1 8- methyl-estra- 1,3,5 10) -triene;

17a (2',3 -dibromomethylene-1',3 ',3-trimethyl-prop-1- en- 1-yl) 17 5- tetrahydropyran-2-yloxy -3-methoxy- 18-methyl-estra- 1,3,5 10 -triene;

17 a- (2',3-dibromomethylenel -methyl-prop- 1 '-en- 1- yl)-17,8-(tetrahydropyran-2'-yloxy)-3-ethoxy-18 methyl-estra-1,3,5(10)-triene;

17w (2',3 '-dibromomethylene-3'-methyl-prop 1 '-en- 1' yl)-17,8-(tetrahydropyran-2-yloxy) -3-ethoxy-18- methyl-estra-1,3,5(10)-triene;

1711-(2,3'-dibrornomethylene- 1,3 -dimethy1-prop-1-en- 1-y1) 175-(tetrahydropyran-2'-yloxy) -3-ethoxy-18- methyl-estra-1,3 ,5 10)-triene;

17oc-( 2',3 -dibromornethylene-3 ',3-dimethyl-prop-1-en- 1 '-y1)-17p-(tetrahydropyran-2-yloxy) -3-eth0xy-18- methyl-estral ,3,5 10 -triene;

171x- 2',3 '-dibromomethylene-1',3 ,3 '-trimethyl-pr0pl en-1'-yl -17/3-(tetrahydropyran-Z-yloxy) -3-ethoxy- 18-methyl-estra-1,3,5(10)-triene.

EXAMPLE 4 This example illustrates methods of preparing 3-deoxy- 17a-dihalomethylene-prop-1'-en-1'-yl steroids which can be used as starting materials for preparing the 3-deoxy compounds of my invention. In this example a solution of 5 g. of 17 3-acetoxy-17a-(2',3'-dichloromethylene-prop- 1 en 1'-yl)-l9-norandrost-4-en-3-one in 100 ml. of glacial acetic acid, containing 5 ml. of 1,2-ethanedithiol and 4 ml. of a saturated solution of hydrogen chloride in acetic acid, is allowed to stand at room temperature for 4 hours. Water is added and the resulting mixture then extracted with ethyl acetate. The extracts are washed with a 5% aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from etherzhexane and 4 g. of this material in 500 ml. of ethanol (previously distilled over Raney nickel) is heated at reflux with 50 g. of Raney nickel for 6 hours. The catalyst is removed by filtration and washed with hot ethanol. The combined washings and filtrate are evaporated to dryness. The residue is dissolved in chloroform and resulting solution is first washed with a dilute aqueous solution of hydrochloric acid, then dilute aqueous carbonate solution and then with water. The washed solution is dried and evaporated to dryness affording a 176 acetoxy-17a-(2,3-dichloromethyleneprop-l'-en-1'-yl)-19-norandrost-4-ene residue which is further purified by recrystallization from acetonezhexane.

By following the above procedure using the corresponding 3-keto-17a-dihalomethylene-prop-1'-en-l-yl steroid as starting materials, the following 3-deoxy compounds are prepared:

17B-acetoxy-17a- (2',3 -dichloromethy1ene-1-methylprop-l-en-1'-yl) l9-norandrost-4-ene; 17B-acetoxy-17a- (2',3 '-dichloromethylene-3 '-met'hylprop-1'-en-1'-yl)-l9-norandrost-4-ene; 17fi-acetoxy- 17w 2', 3 '-dichloromethylene-3',3 '-dimethy1- prop-1'-en-1-yl)-19-norandrost-4-ene; 17fl-acetoxy-17a-(2,3 '-dichloromethylenel ,3 -dirnethylprop-1-en-l-yl) -l9-norandrost-4-ene; 17;3-acetoxy-17w(2',3'-dichloromethylene-1 ,3 ,3 '-trimethyl-prop-1'-en-1'-yl)-l9-norandrost-4-ene; 17 fi-acetoxy- 1 711- 2',3 -dichloromethylene-prop- 1 '-en- 1-yl) -l S-rnethyl-19-norandrost-4-ene; 17/3-acetoxy-17a-(2Q3 '-dichloromethylene- 1 '-methylprop-l-en-1'-yl)-18-methyl-19-norandrost-4-ene; l7B-acetoxy- 17m- 2',3 -dichloromethylene-3 methylprop-1'-en-l'-yl)-18-rnethyl-19-norandrost-4-ene; l7fl-acetoxy-17a- (2',3 '-dichloromethylene-3 ,3'-dimethylprop-l -en-1-yl) -l 8-methyl-l9-norandrost-4-ene; l-acetoxy-l7a-(2,3'-dichloromethylene-1',3'-dimethylpro p- 1 '-en- 1 '-yl) -l 8-methyll9-norandrost-4-ene;

17fi-acetoxy-17a- (2',3 -dichloromethylene-1',3',3 '-trimethy1-prop-1'-en-1'-yl)-18-methyl-19-norandrost- 4-ene;

17 fl-acetoxy- 1 7a- (2',3 '-dichloromethylene-prop-1'-en- 1'-yl -androst-4-ene;

17fi-acetoxy-17a-(2Q3 '-dichloromethylene-1'-methylprop-l -en-l -yl) -androst-4-ene;

17 B-acetoxy- 1 7 oc- (2 ,3 -dichloromethylene-3 '-methylprop-1-en-l-yl)-androst-4-ene;

17fl-acetoxy-17a- 2',3 -dichloromethylene-3,3'-dimethy1- prop-1-en-l'-yl) -androst-4-ene;

17/8-acetoxy-17a-(2',3'-dichlorornethylene-1',3'-dimethylprop-1'-en-1-yl) -androst-4-ene;

17fi-acetoxy-17u-(2',3 -dichloromethylene-1,3,3 '-trimethyl-prop-1'-en-1-yl) -androst-4-ene;

17 ,B-acetoxyl7a- (2',3 '-dichloromethylene-l -methy1- prop-1'-en-1'-yl) -androst-4-ene;

17B-acetoxy-17ot- (2.,3 '-dichloromethylene-3'-methylprop-1-en-1-yl) -androst-4-ene;

1713-acetoxy-17a-(2',3'-dichloromethylene-3',3'-dimethylprop-1-en-1'-yl) -androst-4-ene;

17,8-acetoxy-17a-(2',3 dichloromethylene-l ',3-dimethylprop-1-en-1'-yl) -androst-4-ene;

17,8-acetoxy- 17(1- (2',3 -dichloromethylene-1,3 ',3 trimethyl-prop-1'-en-1'-yl) -androst-4-ene.

By using the corresponding 17,8-hydroxy and 17fi-(tetrahydropyran-2'-yloxy) starting materials in place of the 17fi-acetoxy starting materials used above, the corresponding 17B-hydroxy and 17,9-(tetrahydropyran-2-yloxy) forms of the above 3-desoxy compounds, are respectively, prepared. The corresponding 17a-(dibromomethylene-prop-1'-en-l'-yl);

17a- (difiuoromethylene-prop-l'-en-1'-yl) 17 a-(bromochloromethylene-prop-1-en-1-yl); 17a-(bromofiuoromethylene-prop-1'-en-1'-yl); and 17a-(chlorofluoromethylene-prop-1'-en-1y1) forms of the above 3-desoxy are also respectively prepared, according to the above procedure, for each of the 17,6-acetoxy, 17,8-hydrxy; and 17;8-(tetrahydropyran-2'- yloxy) series, from the corresponding 17 u-(dihalomethylene-prop-1-en-l-yl) starting materials.

EXAMPLE This example illustrates a method of preparing 170cdihalomethylene-prop-l-en-1-yl-steroid 3,17,!3 ethers and 17fi-hydroxy-3-ones. In this example 1.2 ml. of freshly distilled ethyl orthoformate and 0.8 gram of p-toluenesulfonic acid is added to a suspension of 1 gram of 17a- (2',3'-dichloromethylene-prop 1 en-1-yl)-l7[3-(tetrahydropyran-2'-yloxy)-19-norandrost-4-en-3-one in 7.5 m1. of peroxide-free dioxane. The mixture is stirred at room temperature for 15 minutes and allowed to stand at room temperature for an additional 30 minutes, and then 0.8 ml. of pyridine is added. Water is then added to the mixture until precipitation occurs. The resulting precipitate is collected by filtration, washed with water and then air-dried affording a 17a-(2,3'-dichloromethylene-prop-1-en-1'- yl)-3-ethoxy 173 (tetrahydropyran-2-yloxy)-19-n0randrosta3,5-diene residue which is further purified by recrystallization using an acetonezhexane solvent. By following the same procedure, the 3-keto-17fl-(tetrahydropyran-2-yloxy) products of Example 2 are converted, respectively, to the corresponding 17a-(2,3'-dihalomethylene-prop -1' en-1'-yl)-3-eth0xy-17,8-(tetrahydropyran- 2-yloxy)-3,5-diene steroids.

The 17w(2,3'-dichloromethylene-prop 1' en-1'-yl)- 3-ethoxy-l7fi-(tetrahydropyran 2-yloxy)-19-norandrost- 3,5-diene product is divided into two equal portions. One portion is reserved for use in Example 14, and the other portion is dissolved in ml. of acetone. A few drops of aqueous 36% (wt.) hydrochloric acid is then added to the acetone solution. The resulting mixture is then heated for a few minutes at 100 C. and then cooled and diluted with water. The mixture is then filtered and the resultant filter cake dried and further purified by recrystallization from acetonezhexane solvent affording 17a-(2',3'dichl0 romethylene prop 1'-en-1'-yl)-17,8-hydroxy-19 norandrost-4-en-3-one. The other l7fl-(2',3'-dihalomethylene-prop l en-l'-yl)-3-ethoxy-17fl-(tetrahydropyran- 2-yloxy)-3,5-diene steroid products produced above are similarly divided into two portions; one portion is reserved for use in Example 14, and the other portion is converted to the corresponding 17u-(2',3'-dihalomethylene-prop 1' en-1'-yl)-175-l1ydroxy-4-en-3-one steroids, according to the same procedure.

EXAMPLE 6 This example illustrates methods of cleaving 17/3-ester protecting groups to produce 17,8-hydroxy compounds. In this example, a solution of 1 g. of l7 3-acetoxy-17a- (2',3-dichloroethylene-prop-1'-en-1'yl) 3p tetrahydropyran-2-yloxy)-i9-no1androst-4-ene in 50 ml. of methanol is allowed to stand at room temperature for 13 hours with an aqueous 1% (wt.) solution of potassium carbonate in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water to neutrality and dried, yielding a 17m-(2',3-dichloromethylene-prop-1'-en 1'-yl) 17,3 hydroxy 3 ,8 (tetrahydropyran-Z'-yloxy)- 19-n0randrost-4-ene residue which is further purified by recrystallization from methylene chloride2ether.

By following the same procedure, the following 176- hydroxy compounds are prepared from the corresponding 17,6-acetoxy compounds:

17ot-(2',3-dichloromethylene 1' methyl-prop-Y-eml yl) 17 fi-hydroxy-B B- (tetrahydropyr an-2-yloxy) 19- norandrost-4-ene;

17a (2',3' dich1oromethylene-3'-methyl-prop-l'-ena1'- yl) -17,B-hydroxy-3 [3-(tetrahydropyran-2'-yloxy)-19- norandrost-4-ene;

17u-(2',3'-brornochloromethylene 1,3' dimethyl-prop- 1en-1-yl)-17 S-hydroxy-3fl-(tetrahydropyran-2- yloxy)-19-norandrost-4-ene;

17cc (2',3'-bromofluoromethylene1,3,3'-trimethyl-prop- 1'-en-1'-yl)-17 3-hydroxy-3l3- (tetrahydropyran-2'- yloxy)-l9-norandrost-4-ene;

l7oc-(2',3' dibromomethylene 1' methyl-l-en-l-yl)- 17fl-hydroxy- 1 8-methy1-3 B- (tetrahydrOpyran-ZT- yloxy) 19-n0randrost-4-ene;

l7a-(2',3-dibromomethylene-prop l en 1 yl)-17,8-

ihydroxy-3- (tetrahydr0pyran-2'-yloxy -estra- 1,3 5(10)-triene;

17cc (2,3 difluoromethylene 1 methyl-prop-l'-en-1- yl) -17,8-hydroxy-3-(tetrahydropyran-2-yloxy) estra-1,3,5(10)-triene;

17a-(2',3' dibromomethylene 3 methyl-prop-1'-en-1'- yl)-17fi-hydroxy-3-(tetrahydropyran-2'-yloxy)- estra-1,3,5( 10)-triene;

17a-(2',3-chloro 1',3' dimethyl-prop-1-en-l'-yl)-175- hydroxy-3-(tetrahydropyran-2-yloxy)-estra-1,3, 5(10)-triene;

17a-(2',3-bromochloro 3',3' dimethyl-prop-l en-l yl) -17,8-hydroxy-3-(tetrahydropyran-2'-yloxy)-estra- 1,3 ,5 10) -triene;

17u-(2',3-chlorofiuoro 1,3,3' trimethyl-prop-1'-en-1- yl)-17,6-hydroxy-3- (tetrahydropyran-2'-yloxy) -estra- 1,3,5(l0)-triene;

17oz (2',3' dibromomethylene prop-1'-en-1'-y1)-17flhydroxy-18-methyl-3-(tetrahydropyran-2'-yloxy)- estra-1,3,5(10)-triene;

23 EXAMPLE 10 This example illustrates methods of converting 3-'keto- 17B-hydroxy compounds to 3,17B-dihydroxy compounds and 3,l7/3-dihydroxy compounds to 3,17,3-acylates. In this example a solution of 2 g. of lithium tri-t-butoxyaluminum hydride in 30 ml. of tetrahydrofuran is added with stirring to a solution of 2 g. of 17a-(2',3'-dibromomethylene-prop 1 en-1-yl)-17B-hydroxy-19-norandrost-4-en- 3-one in 40 ml. of tetr-ahydrofuran. The mixture is heated under reflux for 15 minutes. The excess reagent is then decomposed by the addition of water and saturated aqueous sodium sulfate solution. The organic phase is separated, dried over sodium sulfate and evaporated, affording a 17a-(2',3' dibromomethylene prop-1'-en-1'-yl-3,B, l7fl-dihydroxy-l9-norandrost-4-ene residue which is further purified by recrystallization from acetonethexane.

By following the same procedure using the corresponding 3-keto-17/8-hydroxy starting materials, -the following 3,17,3-diols are prepared:

17a-(2,3'-dich1oromethylene-1'-methy1-prop-1'-en-l'- yl) -3;3,17fi-dihydroxy-19-norandrost-4-ene;

17oz-(2',3 '-dichloromethylene-3 '-methyl-prop-l'-en-1'- yl)-313,17fl-dihydroxy-19=norandrost-4-ene;

17a (2,3-bromochloromethylene-1,3-dimethyl-prop 1 en-l'-yl)-3/8,17,8-dihydroxy-19*norandrost-4-ene;

17a (2',3' difluorornethylene-3,3'-dimethyl-prop-1- en-1-yl) 8,6,17fl-dihydroxy-19-norandrost-4-ene;

17oz (2.,3'-bromofluoromethylene-1 ',3 ,3'-trimethyl-prop- 1'-en-1'-yl)-3,8,17;9-dihydroxy-19-norandrost-4-ene;

17a- (2,3'-dibromoethylene-prop-1'-en-1-yl) 55, 17,8-

dihydroxy-lS-methyl-19-norandrost-4-ene;

170: (2., 3' dibromomethylene-1'-methyl-prop-1'-en-lyl)-318,l718-dihydroxy-18-rnethyl-19-norandrost-4-ene;

17a (2,3'-bromofiuoromethylene-1',3',3-trimethyl-prop- 1'-en-1-y1)-313,17,6-dihydroxy-18-methyl-19- norandrost-4-ene;

17a-(2',3-dibromomethylene-prop-l'-en-1'-yl) 35,17,8-

dihydroxy-androst-4-ene;

17a- (2,3 -dichloromethylene- -methyl-prop-l '-en-1'- yl) -35, l7B-dihydroxy-androst-4-ene;

17a-(2, '-dichloromethylene-3'-methyl-prop-1-en-1'- yl)-3}8,17fl-dihydroxy-androst-4-ene;

17oz (2.,3-bromochloromethylene-1,3'-dimethyl-prop-1'- en-1'-yl) -3 ,3, l7fl-dihydroxy-androst-4-ene;

17a-( 2',3'-difiuoromethylene-3,3'-dimethyl-propl en-1-yl)-3,8,17B-dihydroxy-androst-4-ene;

171x-(2',3'-dibromomethylene-prop-l-en-1'-yl) 65,175-

dihydroxy-18-methyl-androst-4-ene;

17oz (2',3' dibromomethylene 1'-methyl-prop-1'-en-l'- yl)-3fl,17 8-dihydroxy-18-methyl-androst-4-ene;

17a (2.,3 '-bromofluoromethylene-1',3 ',3'-trimethyl-prop- 1'-en-1'-yl) -3fi,17,9-dihydroxy- 1-8-methyl-androst- 4-ene;

17a-butatrienyl-3B, 17fi-dihydroxy-19-norandrost-4-ene;

3 13, 17,3-dihydroxy-17a- 1'-methyl-butatrien- 1'-yl) 19-norandrost-4-ene;

3 p, 17 B-dihydroxyl7a- (4'-methyl-butatrien-l '-yl) 19-norandrost-4-ene;

3 ,8, 17,8-dihydroxy-17w 1',4'-dimethyl-butatrien-1'-yl) 1-9-norandrost-4-ene;

3/8, l7/8-dihydroxy-17a-(4',4'-dimethyl-butatrien- 1'-yl) -19-norandrost-4-ene;

3fi,17-dihydroxy-17a-( 1',4',4'-trimethyl-butatrien- 1'-yl) -19-norandrost-4-ene;

3n,17 3-dihydroxy-18-methy1-l7a-( 1'-methyl-butatrien- 1-yl) -l9-norandrost-4-ene;

3,3,17B-dihydroxy-l8-methyl-17a-(1',4',4'-trimethylbutatrien-l-yl)19-norandrost-4-ene;

17a-butatrienyl-3,17B-dihydroxy-androst-4-ene;

3p,l7;8-dihydroxy-17a-( 1'-methyl-butatrien-1-y1) androst-4-ene;

3 p, 17.;3-dihydroxy- 1711- 4'-methy1-but atrien-l '-yl) androst-4-ene;

3-,8, 1 7,8-dihydroxy- 17 oc-( 1',4'-dimethyl-butatrien- 1-yl) -androst-4-ene;

3 p, 17,8-dihydroxyl7oz- (4',4'-dimethyl-butatrien- 1'-yl) -androst-4-ene;

3B,17/3-dihydroxy-17a-( l,4',4'-trimethyl-butatrien- 1-yl -androst-4-ene;

3/3, l7fi-dihydroxy-18-methyl-l7a- 1'-methyl-butatrien- 1'-yl) --androst-4-ene;

3B,17 3-dihydroxy-18-methyl-17a-( 1',4,4'-trimethylbutatrien-1'-yl) -androst-4-ene.

One gram of 17a-(2',3'-dibromomethylene-prop-1'-enl-yl)-3B,l7fl-dihydroxy-19-norandrost 4- ene is mixed with 4 m1. of pyridine and 4 ml. of acetic anhydride and heated at 40 for 10 hours. The mixture is then poured into ice Water and the resulting precipitate is collected by filtration. The precipitate is washed with water and dried affording a 3 3,17fi-diacetoxy-17u-(2,3-dibromomethylene-prop-l'-en-1 yl) -19-norandrost-4-ene residue which is further purified by recrystallization using an acetone:hexane solvent. By following the same procedure, the 3,17fl-dihydroxy product produced above are converted to the corresponding 3,17,8-diacetoxy compounds.

EXAMPLE 11 This example illustrates a method of preparing the compounds of Formula I of my invention. In this example 30 ml. of anhydrous ethyl ether containing 1.1 g. of l7a-(2',3dibromomethylene-prop-1'-en-1-yl)-17B-hydroxy-l9-norandrost-4-en-3-one and 1.3 g. of activated magnesium shavings in suspension, is heated at reflux for 48 hours. The mixture is then poured into water containing 10% (wt.) hydrochloric acid. The ethyl ether layer is then separated by decantation, washed neutral with water, and evaporated affording a l7a-butatrienyll7;?3-hydroxy-19-norandrost-4-en-3-one residue which is then further purified by chromatography over alumina sequentially eluting with hexane:benzene mixtures, benzene, and benzenezether mixtures.

By following the above procedure using the corre sponding 17cc (2',3'-dibromomethylene-prop-1'-en-1-yl) steroids as starting materials, the following compounds of Formulas II and III are prepared:

17fi-hydroxy-17u-( 1'-methyl-butatrien-1'-yl) -19- norandrost-4-en-3-one;

17/3-hydroxy-17a-(4-methyl-butatrien-1'-yl) -19- norandrost-4-en-3-one;

17fi-hydroxyl 7 a-( l',4'-dimethyl-butatrienl '-yl) l9- norandrost-4-en-3-one;

17y8-hydroxy- 17 w (4',4-dimethyl-but atrien- 1'-yl) -19- norandrost-4-en-3 -one;

17fi-hydroxy-17a-( 1,4',4-trimethyl-butatrien-1 '-y1) 19-norandrost-4-en-3-one;

l7a-butatrienyl-17B-hydroxy-18 -methy1-9-norandrost- 4-en-3 -one;

l7;8-hydroxy-17a-( 1-methyl-butatrien1'-yl) -18- methyl-19-norandrost-4-en-3-one;

17,8-hydroxy-17a-(4'methy1-butatrien-1'-yl) -18- methyl-19-norandrost-4-en-3-one;

17 B-hydroXy-17u-( 1',4-'-dimethyl-butatrien-1'-y1) 18-methyll9-norandrost-4-en-3 -one;

1713-hydroxy-17u- (4',4'-dimethyl-butatrien-1'-yl) -18 -methyl-19-norandrost-4-en-3-one;

17B-hydroxy-17u-( 1',4',4'-trimethyl-butatrien-1-yl)- 18 -methyl-19-norandrost4-en-3-one;

17 B-acetoxy- 17 rx-butatrienyl- 1i9-norandrost-4-en-3-one;

17fl-acetoxy-17a-( 1'-methyl-butatrien-1'-yl) -19- norandrost-4-en-3-one;

17fl-acetoxy-l7a- (4'-methyl-butatrien-1'-yl) -l 9- norandrost-4-en-3-one;

17 fi-acetoxy- 17 a-( 1',4-'-dimethyl-butatrien-1-yl) 19-norandrost-4-en-3-one;

17 fi-acetoxy-3 -hydroxy-17a-( 1,4', '-trimethyl-butatrien- 1',yl)-estra-1,3,5.(10)-triene;

3-acetoxy- 17a-butatrienyll7fl-hydroxy-estra- 1,3,5

triene;

3acetoxy-17B-hydroxy-17a-( l-methy1-butatrien-1'-yl) estra-1,3,5(10)-triene;

3-acetoxy-l7 3-hydroxy- 17 a-(4'-methyl-butatrien- 1'-yl) estra- 1,3 ,5 10 triene;

3 acetoxy- 17 B-hydroxy-17u- 1 ,4'-dimethyl-butatrien-1'- yl)-estra-1,3,5.(10)-triene;

3-acetoxy-17,3-hydroxy-17a-(4,4-dimethyl-butatrien-1'- yl)-estra-l,3,5(10)-triene;

3-acetoXy-17;3-hydroxy-17a-(1',4,4'-trimethyl-butatrien 1'yl)-estra-1,3,5(10)-triene;

17 8-acetoxy-17a-butatrienyl-3 methoxy-estra-l (3,5 10

triene;

17B-acetoxy-3-methoxy-17u-( 1'-methyl-butadien-1'-yl)- estra-1,3,5 (10)-triene;

17,3-acetoxy-3 -methoxy-17a- (4-methyl-butatrien-1-yl) estra-1,3,5 10)-triene;

17fl-acetoxy-3-methoxy-17a-(1,4-dimethyl-butatrien-1'- yl)-estra-1,3,5.(10)-triene;

17 3-acetoxy-3 methoxy- 17 (x- (4',4'-dimethy1-butatrien-1 yl)-estra-1,3,5(10)-triene;

3-a'cetoxy-17fl-hydroxy- 17 u( 1',4',4'-trimethyl-butatrien- 1-yl)-estra-1,3,5(10)-triene;

3,17,8-diacetoxy-17a-butatrienyl-estra-1,3,5.(10) triene;

3,17,6-diacetoxy-17a-( 1'-methyl-butatrien-1'-yl) estra- 1,3,5 (10) triene;

3,17B-diacetoxy-17a- (4'-methy1-butatrien-1-yl estra- 1,3,5(10)-triene;

3,17fi-diacetoxy-17a-.( 1',4'-dimethyl-butatrien-1'-yl) estra-1,3,5 10)-triene;

3,17/8-diacetoxy17a-(4,4'-dimethyl-butatrien-1'-yl) estra-1,3,5(10)-triene;

3, 1718-diacetoxy- 17 a( 1',4,4'-trimethyl-butatrien-1'-yl)- estra-1,3,5 (10)-triene;

By following the above procedure, the corresponding 18-methyl derivatives of the above estra compounds are also prepared from the corresponding 17a-dibromomethylene-propadienyl-l8-methy1 precursors.

The above compounds of Formulas II and III are also respectively prepared, according to the same procedure, from the corresponding 17a (2', -dichloromethyleneprop l'-en-1'-yl) and 17a-(2-3'-bromofluoromethyleneprop-1'-en-l-yl) steroids.

EXAMPLE 12 This example illustrates methods of preparing the compounds of Formula I of our invention. In this example 10 mmoles of 17a(2',3'-dibromomethylene-prop-1-en-lyl) 17B-(tetrahydropyran-2-yloxy)19-norandrost-4-en- 3-one is added, under a nitrogen atmosphere, to a solution of 50 mmoles of cuprous chloride (CuCl) in 100 ml. of dimethylsulfoxide at C. The mixture is maintained at this temperature for 93 hours, cooled and poured into water. The product is isolated by extraction with methylene dichloride. The residue is dissolved in hexane-benzene (1:1) and chromatographed over alumina eluting with hexane-benzene, benzene, and benzene-ether mixtures to yield 170: butatrienyl-17fi-tetrahydropyran-Z-yloxy)19- norandrost-4-en-3-one. The compounds prepared according to Example 11 are also prepared by the above procedure using each of their corresponding 17u-(2',3-dibromomethylene prop-l'-yl) 17a-(2,3-dichloromethylene prop-1'-yl); 17a-(2',2'-bromochloromethylene-prop- 1'-yl) and 17a (2',3'bromofluoromethylene-prop-1yl) steroid precursors as starting materials.

The above compounds are also prepared according to a first modified procedure wherein after the treatment at 20 C. for 93 hours, the reaction mixture is heated at C. for 32 hours; and also according to a second modified procedure wherein in place of the treatment at 20 C. for 93 hours, the reaction mixture is heated at 80 C. for 18 hours. In each of the modified procedure, the reaction mixture is allowed to cool to room temperature prior to being processed and chromatographed.

EXAMPLE 13 This example illustrates methods of preparing the compounds of Formula II. In this example 1 me. of 17a-.(2',3'- dichloromethylene prop 1-e11-1'-yl)-3,17;8-bis(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is dissolved in 40 ml. of anhydrous ether. The resulting solution is added dropwise, over a 10 minute period, to a mixture of 3 me. of butyl lithium in an anhydrous ether at 35 C. with stirring. The reaction mixture is maintained at 35 C. for an additional hour and then allowed to rise to room temperature (i.e. about 20 C.). The reaction mixture is then poured into water and extracted with methylene chloride. The extracts are combined and washed with water, dried and evaporated to dryness afiording a l7a-butatriene 35,175 bis(tetrahydropyran 2' yloxy)-estra- 1,3,5(10)-triene residue, which is then further purified by chromatography over alumina and recrystallization from hexane acetone.

By following the same procedure using the corresponding 17oz (2',3'-dichloromethylene-prop-1'-en-1'-yl) starting materials, the following compounds are prepared:

17 0L-,( 1-methyl-butatriene-1'-yl)-3,17B-bis(tetrahydropyran-2-yloxy) -estra-1,3,5 10) triene;

175-(4'-methyl-butatrien-1-yl)-3,17B-bis(tetrahydropyran-2'-y1oxy) -estra-1,3,5 10) triene;

17ec-( l,4'-dimethylbutatrien-l yl 3, l7 8-bis (tetrahydropyran-2'-yloxy -estra-l,3,5 10) triene;

17a-(4,4'-dimethyl-butatrien-1'-y1)-3,17(3-bis(tetrahydropyran-2'-yloxy) 'estra-1,3,5 (10)-triene;

17u-( 1',4',4-trimethyl-butatrien-1-yl)3,17 S-bis(tetrahydropyran-2'-yloxy) estra- 1 ,3 ,5 10 triene;

l7a-butatrienyl-18-methyl-3, 17 3-bis(tetrahydropyran- 2'-yloxy)-estra-1,3,5(10)-triene;

18-methyl-17a-( l'-methyl-butatrien-1'-yl)-3,l713-bis (tetrahydropyran-2-yloxy estra- 1,3,5 10)-triene;

18-methy1-17a-(4-methyl-butatrien-1'-yl)-3,l7B-bis tetrahydropyran-2'-yloxy) -estra-1,3 ,5 10) triene;

l8-methyl- 1 t-( l',4'-dimethyl-butatrien-1'-yl) 3 l 7/3-bis- (tetrahydropyran-2'-yloxy)-estra-1,3,5 10 triene;

18-methyl-17ot-(4',4'-dimethyl-butatrien-1'-yl)-3,17B-bis (tetrahydropyran-2-yloxy) -estra-1,3 ,5 10)-triene;

l8-methyl- 1 7a-( 1',4',4'-trimethyl-butatrienl -yl) 3 l 7j3- bis (tetrahydropyran-2-yloxy) -estra-1,3,5 (10)-triene.

The above compounds are also prepared according to the above procedure using the corresponding 17a-(2',3'- dibromomethylene prop 1' en 1' yl); 17o: (2,3'- difiuoromethylene prop 1' en 1' yl); (2,3'- bromofluoromethylene prop 1 en 1' yl); and 17a- (bromochloromethylene prop 1' en 1 yl) steroid starting materials respectively.

EXAMPLE 14 This example illustrates methods of preparing 3-keto compounds of Formula III using 17a-(dihalomethyleneprop-1-en-1-yl)-3,5-diene steroids, having S-ether protecting groups, as starting materials. In this example 1 me. of 17oz (2',3' dibromomethylene prop 1' en- 1' yl) 3 ethoxy (tetrahydropyran 2' yloxy)- 19 norandrosta 3,5 diene is dissolved in 40 ml. of anhydrous ether. The resulting solution is added dropwise, over a 10 minute period, to a mixture of 3 me. of butyl lithium in 100 ml. of anhydrous ether at 35 C., with stirring. The reaction mixture is maintained at 35 C. for an additional hour and then allowed to rise to room temperature (about 20 C.). The reaction mixture is then poured into water and extracted with methylene chloride. The extracts are washed with water, dried and evaporated to dryness, affording a 17a-butatrien-3-ethoxy- 17 3 (tetrahydropyran 2' yloxy) 19 norandrosta- 3,5-diene residue which is then dissolved in 10 ml. of

3 1 3,-175-bis(tetrahydropyran-2-yloxy) -l7a-(4',4'-dimethyl-butatriene-ll-yl)-estra-1,3 ,5 10) -triene; 3,175-bis(tetrahydropyran-2'-yloxy)-17u-( 1',4',4'-trimethyl-butatrien- 1 -yl -estral ,3 ,5 1O -triene; l7a-butatrienyl-3, 1 75-bis(tetrahydropyran-2'-yloxy LS-methyl-estra- 1,3 ,5 10 -triene; 3,l75-bis(tetrahydropyran-2'-yloxy)-18-methyl-17w 1-methyl-butatrien-1'-yl) -estra-l,3 ,5( 10) -triene;

3, l75-bis (tetrahydropyran-2-yloxy)-18-methyl-l7a (4-methyl-butatrien-l yl -estral ,3 ,5 (-l -triene;

3,175-bis(tetrahydropyran-2-yloxy)-l8-methylsl7a- (l,4'-dimethyl-butatrienl -yl) -estral ,3,5( 10) triene;

3,175-bis(tetrahydropyran-2'-yloxy)-l8-methyl-17u- (4',4-dimethyl-butatrien- 1 -yl -estra- 1,3,5 10 triene;

3,l75-bis(tetrahydropyran-2'-yloxy)-18-methyl-l7a- 1',4,4'-trimethyl-butatriena1'-yl)-estra-l,3,5 10

triene;

17a-butatrienyl175- (tetrahydropyran-2-yloxy) -3- methoxy-estra-1,3,5 10)-triene;

175-( tetrahydropyran-2'-yloxy) -3-methoxy-l 7oz lmethyl-butatrienl '-yl -estra-1,3,5 10 -triene;

17 5- (tetrahydropyran-2-yloxy) -3-methoxy- 1 7w (4'- methyl-butatrien-l-yl)-estra-1,3,5()-triene;

17,8-(tetrahydropyran-2'-yloxy) -3-methoxyl7m-( l',4-

dimethyl-butatrienl '-yl -estra- 1, 3 ,5 10 )-triene;

175- (tetrahydropyran-2'-yloxy) -3-methoxy- 17:1- (4',4'-

dimethyl-butatrien-1-yl)-estra1,3,5 10) -triene;

175- (tetrahydropyran-2'-yloxy) -3-methoxy-17a- 1',4,4'-

trimethyl-butatrien-1-yl) -estra-l,3,5 10) -triene;

17a-butatrienyl-175- (tetrahydropyran-2-yloxy)-3- methoxy-18-methyl-estra-l,3 ,5 10) -triene;

175-(tetrahydropyran-2-yloxy) -3 -methoxy-17u-( lmethyl-butatrien-1'-y1)-18-methyl-estra-l,3,5(10)- triene;

175 (tetrahydropyran-Z'-yloxy) -3-methoxy-l 7a- (4'- methyl-butatrien-1-yl)-18-methyl-estra-1,3,5 l0) triene;

175-(tetrahydropyran-2'-yloxy)-3-methoxy-17u-( 1,4'-

dimethyl-b utatrie-nl -yl -1'8-methyl-estra-1, 3 ,5 10') triene;

175 (tetrahydropyran-2'-yloxy) -3-methoxy-17a- (4',4'-

dimethyl-butatrien-l'-yl) -l-8-methyl-estra-1,3,5 1O triene;

175-(tetrahydropyran-2-yloxy) -3-methoxy-17al ,4',4'-trimethyl-butatrien-1'-yl) -l 8 methyl-estra- 1,3,5 10)-triene.

The 3 deoxy 175 (tetrahydropyran 2' yloxy)- 17oz butatrienyl products enumerated in Example 14 are also, respectively, prepared according to the procedure of this example, from each of the corresponding 3-deoxy- 175 (tetrahydropyran 2' yloxy) 17 (2,3' dihalomethylene-propadienyl) starting materials applied according to Example 14.

EXAMPLE 16 This example illustrates methods of converting 17abutatrienyl steroid 3,175-ethers to the corresponding 3,175-diols. In this example 5 mmoles of 17a-butatrienyl- 3,175 bis(tetrahydropyran 2' yloxy) l9 norandrost- 4-ene is added to 50 ml. of an anhydrous methanol solution containing 1% (wt.) oxalic acid at room temperature (20 C.). The mixture is allowed to stand for one hour and is then neutralized by the addition of dilute aqueous sodium bicarbonate solution. The neutralized mixture is poured into water and then filtered. The filter cake is washed with water and then dried affording crude 170cbutatrienyl 3,175 dihydroxy l9 norandrost 4 ene which is further purified by chromatography over alumina eluting with hexane.

By following the above procedure, the 3,175-bis(tetrahydropyran-2'-yloxy) products of Example are converted to the corresponding l7a-butatrienyl-3,l75-diol steroids.

32 EXAMPLE 17 This example illustrates methods of converting 17abutatrienyl steroids having a 3-hydroxy group to the corresponding 3-keto steroids. In this example 10 g. of freshly precipitated manganese dioxide are admixed to a solution of 1 g. of 17a-butatrienyl-3,l75-dihydroxy-l9- norandrost-4-ene in ml. of chloroform. The mixture is stirred at room temperature for 18 hours and then filtered. The filter cake is Washed with hot chloroform and the washings combined with the filtrate and evaporated. The resulting butatrienyl hydroxyl9-norandrost-4-en-3-one residue is further purified by recrystallization from acetone-hexane.

By following the above procedure, the products of Example 16 are converted to the'corresponding 3-keto compounds.

Obviously many modifications and variations of the invention described hereinabove and in the claims can be made without departing from the essence of the scope thereof.

What is claimed is:

1. A compound selected from the group having the formulas:

(III) wherein R is selected from the group consisting of hydroxy, lower alkoxy groups having less than 12 carbon atoms, acid labile ether groups having less than 12 carbon atoms, and carboxylic acyloxy groups having less than 12 carbon atoms; R is selected from the group consisting of hydroxy, acid labile ether groups having less than 12 carbon atoms, and carboxylic acyloxy groups having less than 12 carbon atoms; R R R and R are independent 1y selected from the group consisting of H and lower alkyl; R is selected from the group consisting of H and methyl; and R is selected from the group consisting of 0x0 and the group wherein R is selected from the group consisting of H, hydroxy, lower alkoxy groups having less than 12 carbon atoms, acid labile ether groups having less than 12 carbon atoms, and acyloxy groups having less than 12 carbon atoms.

2. The compound of Formula II of claim 1 wherein R is selected from the group consisting of hydroxy, methoxy, and acetoxy; R is selected from the group consisting of hydroxy and acetoxy; and R R and R are independently selected from the group consisting of H and methyl.

3. The compound of claim 2 wherein said compound is selected from the group consisting of:

3-acetoxy 175 hydroxy 17a (4',4' dimethylbutatrienyl) -estra-1,3,5 10)-triene;

3,175 diacetoxy 17a, (4',4' dimethyl-butatrienyl)- estra-1,3,5(10)-triene;

3,175 dihydroxy 17 (1' Q methyl-bntatrienyl)-v estra-1,3,5(10)-triene',

175 acetoxy 3 hydroxy 17cc (1 methylbutatrienyl) -estra- 1,3,5 10) -triene;

17 3 acetoxy 17 butatrienyl 3 hydroxy-estra- 1,3,5(10)-triene;

17B acetoxy 17a butatrienyl 3 methoxy-estra- 1,3,5(10)-triene;

3,175 diacetoxy 17a butatrien-estra 1,3,5 (10)- triene;

17 butatrienyl 3,175 dihydroxy-estra-1,3,5(10)- triene;

17a butatrienyl 17/3 hydroxy 3 methoxy-estra- 1,3,5(10)-triene; and

3 acetoxy 170a butatrienyl 173 hydroxy-estra- 1,3,5(10)-triene.

4. The compound of Formula III of claim 1 wherein R is selected from the group consisting of hydroxy and acetoxy; R is selected from the group consisting of H and methyl; R R and R are independently selected from the group consisting of H and methyl; and R is selected from the group consisting of 0x0 and the group wherein R is selected from the group consisting of H, hydroxy, and acetoxy.

5. The compound of claim 4 wherein said compound is selected from the group consisting of:

17a-butatrienyl-3 B,l7fi-dihydroxy-19-norandrost-4-ene; 17u-butatrienyl-3 ,9,17 8-dihydroxy-18-methyl-19- n0randrost-4-ene; 17fl-acetoxy-17a-butatrieny1-3p-hydroxy-19- norandrost-4-ene; 17/3-acetoxy-17a-butatrienyl-3,B-hydroxy-18-methyl- 19-norandrost-4-ene; Sfl-acetoxy-l7u-butatrienyl-17,3-hydr0xy-l9- norandrost-4-ene; Sfl-acetoxy-17a-butatrienyl-17/3-hydroxy-18-methyl- 19-norandrost-4-ene; 3/3,17fl-diacetoxy-17a-butatrienyl-19-norandrost-4-ene; 3,6,l7fi-diacetoxy-17a-butatrienyl-l8-methyl-19- norandrost-4-ene; 17u-butatrieny1-17,8-hydr0xy-19-norandrost-4-en-3-one; 17ot-butatrienyl-l7fi-hydr0xy-18-methyl-19-norandrost-4 ene-3-one; 17,9-acetoxy-17a-butatrienyl-19-norandrost-4-en-3-one; 1713-acetoxy-17a-butatrienyl-18-methyl-l9-norandrost- 4-en-3-one;

17a-butatrientyl-l7/8-hydroxy-androst-4-ene;

17 oz-butatrienyl-1'7B-hydroxy-18-methyl-androst-4-ene;

17,8-acetoxy-17u-butatrienyl-androst-4-ene;

17,8-acetoxy-17u-butatrienyl-18-methyl-androst-4-ene;

17 fi-hydroxy- 17 or (4',4-dimethyl-butatrienyl)-19- norandr0st-4'en-3-one;

17 ,8-hydroxy-17a-(4',4'-dimethyl-butatrienyl)-l8- methyl-l9-norandrost-4-en-3-one;

17,8-acetoXy-17a-(4,4'-dimethyl-butatrienyl)-19- norandrost-4-en-3-one;

17fl-acetoxy-17a-(4,4'-dimethyl-butatrienyl)-18- methyl-19-norandrost-4-en-3-one;

l7 3-hydroxy-l7a-( 1'-methyl-butatrienyl) -19- norandrost-4-en-3-one;

17,8-hydroxy-17a- 1'-methyl-butatrienyl)-18-methy1- 19-norandrost-4-en-3-one;

17,8-acet0xy- 17 zx-( 1'-methyl-butatrienyl)-19-noranddrost-4-en-3-one;

17fi-acetoxy-17a-( 1-methyl-butatrienyl)-18-methyl- 19-norandrost-4-en-3-one;

17 fl-hydroxy-17a-( 1,4,4'-trimethy1-butatrienyl) 19- norandrost-4-en-3-one;

1 7p-hydroxy- 17 a- 1',4,4'-trimethyl-butatrienyl)-18- methyl-19-norandrost-4-en-3-one;

17fi-acetoxy-17a-( 1',4',4-trimethy1-butatrienyl)- 19-norandrost-4-en-3-one; and

17fl-acetoxy-l7a- 1 ',4',4'-trimethyl-butatrien-l8- methyl-19-norandrost-4-en-3-one.

6. The compound of claim 5 wherein said compound is selected from the group consisting of:

References Cited UNITED STATES PATENTS 7/1968 Edwards et a1. 260-23955 7/ 1968 Edwards et a1. 260239.55

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 

